Progranulin and Tau Gene Mutations Both as Cause for Dementia:  17q21 Finally Defined

Frontotemporal dementia (FTD) is the second most common form of dementia, second to Alzheimer disease, in persons under 65 years of age. It manifests as a clinically progressive disorder with language impairment, affecting expression and comprehension; behavioral and personality changes; perseveration; apathy; irritability; and disinhibition; progressing to general cognitive impairment.^1- 2 It is associated with significant atrophy with neuronal degeneration in the frontal and/or temporal lobes. Frontotemporal dementia has been described with the presence of ubiquitin-immunoreactive neuronal inclusions without tau pathology and is referred to as FTD with ubiquitin inclusions (FTDU).^3- 4 The composition of the neuronal cytoplasmic inclusions, other than being ubiquinated, is not known.^3- 4 Mutations in the gene encoding the microtubule-associated protein tau gene (MAPT) linked to chromosome 17q21 have been known to produce familial FTD associated with parkinsonism, amyotrophy, disinhibition, and dementia (FTDP-17).⁵ The MAPT mutations are associated with cytoplasmic neurofibrillary inclusions composed of hyperphosphorylated tau.⁵ Of note, in multiple FTD families with linkage to the same region on chromosome 17q21, MAPT mutations have not been identified and the neuropathologic findings do not include tau-immunoreactive inclusion pathology.^3- 4 Rather, these families have ubiquitin-immunoreactive neuronal cytoplasmic inclusions with associated lentiform ubiquitin-immunoreactive neuronal intranuclear inclusions.^3- 4,6- 7 Thus 2 inherited forms of FTD with similar phenotypes have been mapped to 17q21, one linked to MAPT mutations with tau inclusions and the other not linked to MAPT with ubiquitin inclusions.